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Infantile spasms as the initial symptom of biotinidase deficiency
The Journal of Pediatrics Volume 124, Number 1
Kalayci et al.
103
Infantile spasms as the initial symptom of biotinidase deficiency O m e r Kalayci, MD, Turgay Coskun, MD, Ayseg[~l Tokatli, MD, Ercan Demir, MD, G[~liz Erdem, MD, C e m a l G[~ngOr, MD, Ayfer Y0kselen, MD and Imran (3zalp, MD From the Departments of Pediatrics and of Metabolism and Nutrition, Hacettepe Children's Hospital, Ankara, Turkey Two patients with biotinidase deficiency had diagnoses of infantile spasms m a d e at I month of age. Biotinidase deficiency may be seen early in the neonatal period without the characteristic findings such as alopecia and seborrheic dermatitis. This diagnosis should be considered in patients with infantile spasms. (J PEDIATR1994;124:103-4)
Carboxylases are enzymes t h a t fix carbon dioxide. Each of the four carboxylases is synthesized in an inactive form
called an apocarboxylase and becomes enzymatically active only when it is linked covalently to biotin; it is then called holocarboxylase.1 T h e multiple carboxylase deficiencies are genetically determined or acquired disorders of biotin metabolism and result in impaired activity of the biotindependent carboxylases. Two forms of inherited multiple carboxylase deficiencies are caused by distinct enzymatic deficiencies. T h e neonatal form is usually the result of holocarboxylase synthase deficiency, whereas biotinidase deficiency is responsible for the later infantile-onset form. 2 W e report two patients in whom infantile spasms developed at 1 m o n t h of age and who were found to have biotinidase deficiency. CASE REPORTS Patient 1. A 91-day-old male infant was first admitted to the hospital with difficulty in feeding and a generalized squamous rash. Family history disclosed that one pregnancy had resulted in a spontaneous abortion; another child had hypoxic ischemic encephalopathy and died at the age of 5 months after persistent convulsions. Patient 1, born after an uneventful pregnancy to parents who were first-degree relatives, was free of complaints until the age of 1 month, when muscle jerks were first noted; these increased in frequency and severity with time. During this time the patient had two episodes of pneumonia that were treated on an outpatient basis. The patient had received -one dose of diphtheria-pertussis-tetanus vaccine without any complications. The patient was first hospitalized at another institution when a right focal convulsion was noted. An Submitted for publication July21,1993; accepted Aug. 20, 1993. Reprint requests: Omer Kalayci, MD, Bahgelievler 39. sokak 12/6, 06500 Ankara, Turkey. Copyright © 1994 by Mosby-Year Book, Inc. 0022-3476/94/$1.00 + .10 9/22/51167
electroencephalogram showed the presence of a multifocal epileptiform abnormality characterized by burst suppressions. A computed tomographic scan of the brain was normal. An increase in alanine was noted in the urine. Infantile spasms were diagnosed, and the patient was treated with corticotropin and phenobarbital. The convulsions subsided partially. Ten days after discharge the patient was admitted to our hospital. He was lethargic and hypotonic; hyperpnea and frequent muscle jerks were present. Among the most remarkable findings were generalized alopecia of the scalp and seborrheic dermatitis. Ophthalmologic examination revealed optic atrophy and keratoconjunctivitis of both eyes. Fine, crepitant rales were audible in both lung fields, and bronchopneumonia was noted on chest radiographs. Blood pH was 7.25, and the bicarbonate level was 7.3 mmol/L. Clinically, a presumptive diagnosis of biotinidase deficiency was entertained, and biotin therapy was instituted. The serum ammonia level was normal. The lactic acid level was increased in serum (94.3 mg/dl; normal, 14 to 20 mg/dl) and in cerebrospinal fluid (90.0 mg/dl). The pyruvic acid level also was increased in serum (6.0 mg/dl; normal, 0.5 to 1.0 mg/dl). Brainstem auditory evoked potential studies showed no response on the left side and only a low-amplitude response on the right side. Study of visual evoked potentials showed prolonged P1 latencies on both sides. The patient's condition responded promptly to administration of biotin; blood pH and bicarbonate values reverted to normal within 6 hours. The seborrheic dermatitis improved shortly after treatment and was undetectable at the end of 10 days. Biotinidase activity was later shown to be absent. On follow-up examination at 11 months of age, the patient was doing well and had not experienced any convulsions during this period. Neurologic examination did not reveal any abnormalities. However, the patient's Mental score on the Bayley Scales of Infant Development was compatible with 5 months of age. Although there was severe impairment before treatment, brain-stem auditory evoked potential was normal on both sides at this follow-up examination. The electroencephalogram was also normal, and the phenytoin dose was gradually tapered and then discontinued. Patient 2. A 70-day-old female infant was referred to our hos-
104
Kalayci et al.
pital because of uncontrollable convulsions. She was the second child of parents who were third-degree relatives and had one healthy 9-year-old sibling. The mother's pregnancy was uneventful, and the infant did well until 1 month of age, when she started to experience jerky movements of her limbs. She was hospitalized at another institution and received phenobarbital and sodium valproate, which had no effect on the convulsions. An electroencephalogram was reported to show a n epileptiform disorder; treatment with corticotropin was started, and the presumptive diagnosis of infantile spasms was made. The number of convulsions decreased to one per day, and the patient was referred to our hospital for further evaluation. At our hospital an electroencephalogram showed a generalized chaotic baseline pattern and paroxysmal activity in the left hemisphere, but no hypsarrhythmia was observed. A computed tomographic scan and magnetic resonance image of the brain were interpreted as normal. The alanine level was increased in the urine. The patient was hospitalized for the treatment of intractable convulsions. Physical examination revealed a lethargic and hypotonic child with sudden jerky movements of the limbs. Scalp hair was sparse. She was given antibiotics for treatment of pneumonia. On the tenth day of hospitalization, profound metabolic acidosis developed; blood pH was 6.98, and the serum bicarbonate level was 3.4 mmol/L. Biotinidase deficiency was considered as a diagnostic possibility, and biotin was given orally, which resulted in abatement of the acidosis within hours. The serum ammonia level was normal. Serum levels of both lactic acid (79.3 mg/dl) and pyruvic acid (5.6 mg/dl) were increased. The brain-stem auditory evoked potential study showed no response on either side; visual evoked potential findings were normal. Biotinidase activity subsequently was found to be absent. On follow-up examination at 5 months of age, the patient's physical and neurologic examination findings were normal, and she had had not convulsions after initiation of treatment. However, the infant's Mental score on the Bayley Scales was compatible with an age of only 2 months. Brain-stem auditory evoked potential was unresponsive on the left-side, and only a low-amplitude response could be obtained on the right side. An electroencephalogram showed generalized minimal baseline irregularity. The patient is not currently receiving any anticonvulsant drugs. DISCUSSION Biotinidase deficiency is usually responsible for the lateonset form of multiple carboxylase deficiency, 3, 4 and children with this enzymatic deficiency begin to have symptoms after 3 to 4 months of age. 5 Failure to diagnose the disease early in its course may result in severe neurologic sequelae and may lead to death. Thus it is of utmost importance to recognize the disease before it progresses beyond the early stage. Affected patients may have neurologic, cutaneous, or respiratory problems without metabolic acidosis. 6 In both patients with early onset of symptoms, a diagnosis of infan-
The Journal of Pediatrics January 1994
tile spasms had been made. The electroencephalogram may not be typical of hypsarrhythmia early in the course of infantile spasms7; absence of the typical pattern does not alter the diagnostic or therapeutic approach. 8 In both of our patients, the clinical manifestations and electroencephalographic findings, together with a beneficial effect of corticotropin on the convulsions, led the physicians to the diagnosis of infantile spasms before acidosis, the major metabolic manifestation of the underlying disease, became apparent. Neurologic symptoms appeared in both patients before other findings of the disease. Thus biotinidase deficiency, an easily treatable condition, should be considered in the differential diagnosis of infantile spasms, regardless of the age of the patient, especially when the characteristic hypsarrhythmic pattern is absent on an electroencephalogram, even if the patient has a favorable response to treatment with corticotropin. The search for other hallmarks of the disease, especially alopecia and dermatitis, should be meticulous. Biotinidase deficiency is not as rare as was once thought. 9 Because muscle jerks apparently may be the only symptom early in infancy, determination of biotinidase activity, which is inexpensive and easy to perform, 3 should be carried out in such patients even when other signs, such as alopecia, seborrheic dermatitis, and acidosis, are not evident.
REFERENCES
1. Nyhan WL. Inborn errors of biotin metaboiism. Arch Dermatol 1987;123:1696-8. 2. Baumgartner R. Biotin-responsive multiple carboxylase deficiency. In: Fernandes J, Saudubray JM, Tada G, eds. Inborn metabolic diseases. Berlin: Springer Verlag, 1990:311-20. 3. Heard GS, Wolf B, Jefferson LG, et al. Neonatal screening for biotinidase deficiency: results of a 1-year pilot study. J PEDIATe 1986;108:40-6. 4. Wolf B, Grier RE, Allen R J, Goodman SI, Kien CL. Biotinidase deficiency: the enzymatic defect in late-onset multiple carboxylase deficiency. Clin Chim Acta 1983;131:273-81. 5. Wolf B, Grier RE, Allen R J, et al. Phenotypic variation in biotinidase deficiency. J PEDIATR 1983;103:233-41. 6. Tokatli A, Co§kun T, Ozalp I, Giinay M. The major presenting symptom in a biotinidase-deficient patient: laryngeal stridor. J Inherit Metab Dis 1992;15:281-2. 7. Livingston S, Eisner V, Pauli L. Minor motor epilepsy. Pediatrics 1958;21:916. 8. Swaiman KF. Myoclonic epilepsy. In: Swaiman KF, ed. Pediatric neurology: principles and practice. St. Louis: CV Mosby, 1989:423. 9. Co§kun T, Tokatli A, Kocaba§ CN, Topalo~lu H, Topsu M, Ozalp I. Inborn errors of biotin metabolism [Abstract book]. Joint Convention of the Fourth Meeting of the Mediterranean Association of Child Neurology and the First Turkish Child Neurology Congress, Ankara, Turkey, May 28-30, 1992.
Kalayci et al.
103
Infantile spasms as the initial symptom of biotinidase deficiency O m e r Kalayci, MD, Turgay Coskun, MD, Ayseg[~l Tokatli, MD, Ercan Demir, MD, G[~liz Erdem, MD, C e m a l G[~ngOr, MD, Ayfer Y0kselen, MD and Imran (3zalp, MD From the Departments of Pediatrics and of Metabolism and Nutrition, Hacettepe Children's Hospital, Ankara, Turkey Two patients with biotinidase deficiency had diagnoses of infantile spasms m a d e at I month of age. Biotinidase deficiency may be seen early in the neonatal period without the characteristic findings such as alopecia and seborrheic dermatitis. This diagnosis should be considered in patients with infantile spasms. (J PEDIATR1994;124:103-4)
Carboxylases are enzymes t h a t fix carbon dioxide. Each of the four carboxylases is synthesized in an inactive form
called an apocarboxylase and becomes enzymatically active only when it is linked covalently to biotin; it is then called holocarboxylase.1 T h e multiple carboxylase deficiencies are genetically determined or acquired disorders of biotin metabolism and result in impaired activity of the biotindependent carboxylases. Two forms of inherited multiple carboxylase deficiencies are caused by distinct enzymatic deficiencies. T h e neonatal form is usually the result of holocarboxylase synthase deficiency, whereas biotinidase deficiency is responsible for the later infantile-onset form. 2 W e report two patients in whom infantile spasms developed at 1 m o n t h of age and who were found to have biotinidase deficiency. CASE REPORTS Patient 1. A 91-day-old male infant was first admitted to the hospital with difficulty in feeding and a generalized squamous rash. Family history disclosed that one pregnancy had resulted in a spontaneous abortion; another child had hypoxic ischemic encephalopathy and died at the age of 5 months after persistent convulsions. Patient 1, born after an uneventful pregnancy to parents who were first-degree relatives, was free of complaints until the age of 1 month, when muscle jerks were first noted; these increased in frequency and severity with time. During this time the patient had two episodes of pneumonia that were treated on an outpatient basis. The patient had received -one dose of diphtheria-pertussis-tetanus vaccine without any complications. The patient was first hospitalized at another institution when a right focal convulsion was noted. An Submitted for publication July21,1993; accepted Aug. 20, 1993. Reprint requests: Omer Kalayci, MD, Bahgelievler 39. sokak 12/6, 06500 Ankara, Turkey. Copyright © 1994 by Mosby-Year Book, Inc. 0022-3476/94/$1.00 + .10 9/22/51167
electroencephalogram showed the presence of a multifocal epileptiform abnormality characterized by burst suppressions. A computed tomographic scan of the brain was normal. An increase in alanine was noted in the urine. Infantile spasms were diagnosed, and the patient was treated with corticotropin and phenobarbital. The convulsions subsided partially. Ten days after discharge the patient was admitted to our hospital. He was lethargic and hypotonic; hyperpnea and frequent muscle jerks were present. Among the most remarkable findings were generalized alopecia of the scalp and seborrheic dermatitis. Ophthalmologic examination revealed optic atrophy and keratoconjunctivitis of both eyes. Fine, crepitant rales were audible in both lung fields, and bronchopneumonia was noted on chest radiographs. Blood pH was 7.25, and the bicarbonate level was 7.3 mmol/L. Clinically, a presumptive diagnosis of biotinidase deficiency was entertained, and biotin therapy was instituted. The serum ammonia level was normal. The lactic acid level was increased in serum (94.3 mg/dl; normal, 14 to 20 mg/dl) and in cerebrospinal fluid (90.0 mg/dl). The pyruvic acid level also was increased in serum (6.0 mg/dl; normal, 0.5 to 1.0 mg/dl). Brainstem auditory evoked potential studies showed no response on the left side and only a low-amplitude response on the right side. Study of visual evoked potentials showed prolonged P1 latencies on both sides. The patient's condition responded promptly to administration of biotin; blood pH and bicarbonate values reverted to normal within 6 hours. The seborrheic dermatitis improved shortly after treatment and was undetectable at the end of 10 days. Biotinidase activity was later shown to be absent. On follow-up examination at 11 months of age, the patient was doing well and had not experienced any convulsions during this period. Neurologic examination did not reveal any abnormalities. However, the patient's Mental score on the Bayley Scales of Infant Development was compatible with 5 months of age. Although there was severe impairment before treatment, brain-stem auditory evoked potential was normal on both sides at this follow-up examination. The electroencephalogram was also normal, and the phenytoin dose was gradually tapered and then discontinued. Patient 2. A 70-day-old female infant was referred to our hos-
104
Kalayci et al.
pital because of uncontrollable convulsions. She was the second child of parents who were third-degree relatives and had one healthy 9-year-old sibling. The mother's pregnancy was uneventful, and the infant did well until 1 month of age, when she started to experience jerky movements of her limbs. She was hospitalized at another institution and received phenobarbital and sodium valproate, which had no effect on the convulsions. An electroencephalogram was reported to show a n epileptiform disorder; treatment with corticotropin was started, and the presumptive diagnosis of infantile spasms was made. The number of convulsions decreased to one per day, and the patient was referred to our hospital for further evaluation. At our hospital an electroencephalogram showed a generalized chaotic baseline pattern and paroxysmal activity in the left hemisphere, but no hypsarrhythmia was observed. A computed tomographic scan and magnetic resonance image of the brain were interpreted as normal. The alanine level was increased in the urine. The patient was hospitalized for the treatment of intractable convulsions. Physical examination revealed a lethargic and hypotonic child with sudden jerky movements of the limbs. Scalp hair was sparse. She was given antibiotics for treatment of pneumonia. On the tenth day of hospitalization, profound metabolic acidosis developed; blood pH was 6.98, and the serum bicarbonate level was 3.4 mmol/L. Biotinidase deficiency was considered as a diagnostic possibility, and biotin was given orally, which resulted in abatement of the acidosis within hours. The serum ammonia level was normal. Serum levels of both lactic acid (79.3 mg/dl) and pyruvic acid (5.6 mg/dl) were increased. The brain-stem auditory evoked potential study showed no response on either side; visual evoked potential findings were normal. Biotinidase activity subsequently was found to be absent. On follow-up examination at 5 months of age, the patient's physical and neurologic examination findings were normal, and she had had not convulsions after initiation of treatment. However, the infant's Mental score on the Bayley Scales was compatible with an age of only 2 months. Brain-stem auditory evoked potential was unresponsive on the left-side, and only a low-amplitude response could be obtained on the right side. An electroencephalogram showed generalized minimal baseline irregularity. The patient is not currently receiving any anticonvulsant drugs. DISCUSSION Biotinidase deficiency is usually responsible for the lateonset form of multiple carboxylase deficiency, 3, 4 and children with this enzymatic deficiency begin to have symptoms after 3 to 4 months of age. 5 Failure to diagnose the disease early in its course may result in severe neurologic sequelae and may lead to death. Thus it is of utmost importance to recognize the disease before it progresses beyond the early stage. Affected patients may have neurologic, cutaneous, or respiratory problems without metabolic acidosis. 6 In both patients with early onset of symptoms, a diagnosis of infan-
The Journal of Pediatrics January 1994
tile spasms had been made. The electroencephalogram may not be typical of hypsarrhythmia early in the course of infantile spasms7; absence of the typical pattern does not alter the diagnostic or therapeutic approach. 8 In both of our patients, the clinical manifestations and electroencephalographic findings, together with a beneficial effect of corticotropin on the convulsions, led the physicians to the diagnosis of infantile spasms before acidosis, the major metabolic manifestation of the underlying disease, became apparent. Neurologic symptoms appeared in both patients before other findings of the disease. Thus biotinidase deficiency, an easily treatable condition, should be considered in the differential diagnosis of infantile spasms, regardless of the age of the patient, especially when the characteristic hypsarrhythmic pattern is absent on an electroencephalogram, even if the patient has a favorable response to treatment with corticotropin. The search for other hallmarks of the disease, especially alopecia and dermatitis, should be meticulous. Biotinidase deficiency is not as rare as was once thought. 9 Because muscle jerks apparently may be the only symptom early in infancy, determination of biotinidase activity, which is inexpensive and easy to perform, 3 should be carried out in such patients even when other signs, such as alopecia, seborrheic dermatitis, and acidosis, are not evident.
REFERENCES
1. Nyhan WL. Inborn errors of biotin metaboiism. Arch Dermatol 1987;123:1696-8. 2. Baumgartner R. Biotin-responsive multiple carboxylase deficiency. In: Fernandes J, Saudubray JM, Tada G, eds. Inborn metabolic diseases. Berlin: Springer Verlag, 1990:311-20. 3. Heard GS, Wolf B, Jefferson LG, et al. Neonatal screening for biotinidase deficiency: results of a 1-year pilot study. J PEDIATe 1986;108:40-6. 4. Wolf B, Grier RE, Allen R J, Goodman SI, Kien CL. Biotinidase deficiency: the enzymatic defect in late-onset multiple carboxylase deficiency. Clin Chim Acta 1983;131:273-81. 5. Wolf B, Grier RE, Allen R J, et al. Phenotypic variation in biotinidase deficiency. J PEDIATR 1983;103:233-41. 6. Tokatli A, Co§kun T, Ozalp I, Giinay M. The major presenting symptom in a biotinidase-deficient patient: laryngeal stridor. J Inherit Metab Dis 1992;15:281-2. 7. Livingston S, Eisner V, Pauli L. Minor motor epilepsy. Pediatrics 1958;21:916. 8. Swaiman KF. Myoclonic epilepsy. In: Swaiman KF, ed. Pediatric neurology: principles and practice. St. Louis: CV Mosby, 1989:423. 9. Co§kun T, Tokatli A, Kocaba§ CN, Topalo~lu H, Topsu M, Ozalp I. Inborn errors of biotin metabolism [Abstract book]. Joint Convention of the Fourth Meeting of the Mediterranean Association of Child Neurology and the First Turkish Child Neurology Congress, Ankara, Turkey, May 28-30, 1992.